Interstitial brachytherapy for recurrent breast cancer using a high dose rate lr-192 remote afterloading system: a report of two cases

We employed interstitial brachytherapy using a high dose rate Ir-192 remote afterloading unit in two breast cancer patients with locoregional recurrence. In the first case, skin metastasis was treated, with favorable control of the infield tumor but subsequent persistent sequelae and multiple outfield metastases. This experience caused us to be cautious when choosing brachytherapy for the second case, in whom a solitary metastasis to an axillary lymph node was successfully treated. Although this method is still investigational, it may play a critical role in the treatment of locoregional recurrence resistant to other treatment modalities.     

Stage-dependent benefits and risks of pimobendan in mice with genetic dilated cardiomyopathy and progressive heart failure

Background and Purpose

The Ca²⁺ sensitizer pimobendan is a unique inotropic agent that improves cardiac contractility with less of an increase in oxygen consumption and potentially fewer adverse effects on myocardial remodelling and arrhythmia, compared with traditional inotropes. However, clinical trials report contradictory effects of pimobendan in patients with heart failure (HF). We provide mechanistic experimental evidence of the efficacy of pimobendan using a novel mouse model of progressive HF.

Experimental Approach

A knock-in mouse model of human genetic dilated cardiomyopathy, which shows a clear transition from compensatory to end-stage HF at a fixed time during growth, was used to evaluate the efficacy of pimobendan and explore the underlying molecular and cellular mechanisms.

Key Results

Pimobendan prevented myocardial remodelling in compensated HF and significantly extended life span in both compensated and end-stage HF, but dose-dependently increased sudden death in end-stage HF. In cardiomyocytes isolated from end-stage HF mice, pimobendan induced triggered activity probably because of early or delayed afterdepolarizations. The L-type Ca²⁺ channel blocker verapamil decreased the incidence of triggered activity, suggesting that this was from over-elevated cytoplasmic Ca²⁺ through increased Ca²⁺ entry by PDE3 inhibition under diminished sarcoplasmic reticulum Ca²⁺ reuptake and increased Ca²⁺ leakage from sarcoplasmic reticulum in end-stage HF.

Conclusions and Implications

Pimobendan was beneficial regardless of HF stage, but increased sudden cardiac death in end-stage HF with extensive remodelling of Ca²⁺ handling. Reduction of cytoplasmic Ca²⁺ elevated by PDE3 inhibition might decrease this risk of sudden cardiac death.     

Differential effects of the formin inhibitor SMIFH2 on contractility and Ca2+ handling in frog and mouse cardiomyocytes

Genetic mutations in actin regulators have been emerging as a cause of cardiomyopathy, although the functional link between actin dynamics and cardiac contraction remains largely unknown. To obtain insight into this issue, we examined the effects of pharmacological inhibition of formins, a major class of actin-assembling proteins. The formin inhibitor SMIFH2 significantly enhanced the cardiac contractility of isolated frog hearts, thereby augmenting cardiac performance. SMIFH2 treatment had no significant effects on the Ca²⁺ sensitivity of frog muscle fibers. Instead, it unexpectedly increased Ca²⁺ concentrations of isolated frog cardiomyocytes, suggesting that the inotropic effect is due to enhanced Ca²⁺ transients. In contrast to frog hearts, the contractility of mouse cardiomyocytes was attenuated by SMIFH2 treatment with decreasing Ca²⁺ transients. Thus, SMIFH2 has opposing effects on the Ca²⁺ transient and contractility between frog and mouse cardiomyocytes. We further found that SMIFH2 suppressed Ca²⁺-release via type 2 ryanodine receptor (RyR2); this inhibitory effect may explain the species differences, since RyR2 is critical for Ca²⁺ transients in mouse myocardium but absent in frog myocardium. Although the mechanisms underlying the enhancement of Ca²⁺ transients in frog cardiomyocytes remain unclear, SMIFH2 differentially affects the cardiac contraction of amphibian and mammalian by differentially modulating their Ca²⁺ handling.     

Preferential antitumor effect of the Src inhibitor dasatinib associated with a decreased proportion of aldehyde dehydrogenase 1-positive cells in breast cancer cells of the basal B subtype

Background  

Recent studies have suggested that the Src inhibitor dasatinib preferentially inhibits the growth of breast cancer cells of the basal-like subtype. To clarify this finding and further investigate combined antitumor effects of dasatinib with cytotoxic agents, a panel of breast cancer cell lines of various subtypes was treated with dasatinib and/or chemotherapeutic agents.     

Protective effect of 16,16-dimethyl prostaglandin E2 on isolated rat hepatocytes against complement-mediated immune attack

16,16-Dimethyl prostaglandin E₂ was examined for its ability to inhibit complement-mediatedin vitro hepatocytolysis by an antigen-antibody reaction. In the presence of fresh rat serum as a source of complement, 5-min culture of isolated rat hepatocytes with a monoclonal antibody against a rat liver-specific membranous antigen resulted in a marked, significant elevation in lactate dehydrogenase leakage into the culture medium. However, with heat-inactivated rat serum, such a reaction did not occur, indicating that the hepatocytolysis induced by the antibody was attributable to the membrane damaging action of complement activated by an antigen-antibody reaction. Pretreatment of the hepatocyte with 16,16-dimethyl prostaglandin E₂ significantly suppressed the cytolytic reaction induced by the antibody in a concentration-dependent manner. These results show that 16,16-dimethyl prostaglandin E₂ is capable of protecting isolated rat hepatocytes against the membrane-damaging insult of activated complement.     

Biomarkers, tumor markers and prognostic markers in breast cancer

Biomarkers are measured in the management of breast cancer patients for the following purposes: (1) early detection, (2) monitoring of advanced breast cancer patients, (3) prediction of prognosis, and (4) prediction of therapeutic response. Summarized results investigated by the Study Group of the Japanese Breast Cancer Society in 2001 concerning the present status of tumor marker measurement in Japan and usefulness of tumor markers for the evaluation for therapeutic response are presented. Significance of two prognostic markers, vessel invasion and HER2 status were discussed at the 9th St Gallen International Consensus Meeting in 2005. Current status, clinical significance, problems and future directions on predictive markers for response to endocrine therapy and cytotoxic chemotherapy are also discussed.     

Estimation of HbA1c response to sitagliptin by change in glycated albumin level for 2 weeks

Aims/Introduction: Since glycated albumin (GA) reflects shorter‐term (about 2 weeks) control of plasma glucose levels compared with HbA1c, GA is thought to be a useful glycemic control indicator for the early period following commencement of the treatment of diabetes. In this study, we attempted to estimate HbA1c using the change in GA level before and after the first 2 weeks (ΔGA2w) of administration of sitagliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor. Materials and Methods: The study included 28 patients with type 2 diabetes who were administered sitagliptin at a dose of 50 mg/day for 12 weeks. Results: At 2 weeks after administration of sitagliptin, GA markedly decreased, while HbA1c had only slightly decreased. A significant positive correlation was observed between the ΔGA2w and the change in HbA1c before and after the first 12 weeks of administration of sitagliptin (ΔHbA1c12w) (R = 0.793, P < 0.0001). The latter was about 0.6 times the former. The estimated HbA1c after 12 weeks of therapy was calculated by adding ΔGA2w × 0.6 to the baseline HbA1c. A significant positive correlation was observed between the estimated HbA1c and the measured HbA1c after 12 weeks (R = 0.735, P < 0.0001) and both were similar levels. Conclusions: HbA1c in the first 12 weeks after administration of sitagliptin could be estimated from the formula using the ΔGA2w. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00167.x, 2011)     

Teratogenicity study of 2,2,3,3,3-pentafluoro-1-propanol (5FP) in rats by oral administration

Teratogenicity of 2,2,3,3,3-pentafluoro-1-propanol (5FP), an alternative cleaning agent for chlorofluorocarbon, was examined in rats. 5FP was diluted with sesame oil and given to pregnant rats (Crj: Wistar) by gavage once a day from day 7 to 17 of pregnancy at doses of 0, 250, 500 and 1000 mg/kg/day. The pregnant rats were sacrificed on day 20 of pregnancy and their fetuses were examined for malformation. In the pregnant rats, 5FP caused wheezing, salivation, ptosis, reduced body weight gain and reduced food consumption at 500 and 1000 mg/kg/day. In the fetuses, 5FP reduced body weight, increased the incidences of skeletal variations and retarded the ossification at 1000 mg/kg/day, but did not increase the incidences of malformations. It was concluded from these results that 5FP has no teratogenicity in rats when given by gavage. The no-observed-adverse-effect level was 500 mg/kg/day for rat fetuses, and 250 mg/kg/day for pregnant rats.     

Metabolism and excretion of 2-nitro-p-cresol in rats

Metabolism of 2-nitro- p-cresol (NPC), an important commercial chemical, was studied in female Sprague-Dawley rats, using (14)C-NPC. It was found that NPC was rapidly absorbed and excreted after an oral dose of 250 mg/kg. Approximately 90% of the administered dose was excreted into urine and less than 10% of the dose into feces for 5 days. Urinary and fecal excretion were found to the same extent after 48 h. Bile excretion amounted to approximately 25% for 2 days. Blood levels of (14)C-NPC reached the maximum concentration (39.4 micro g-equivalents/g) within 1 h, and decreased bi-exponentially. The apparent half-lives of (14)C-NPC were 3.8 h for the rapid phase and 37 h for the slow phase, respectively. From studying the distribution in organs at 1.5, 6, 24, 72 and 120 h, we found that the concentrations of radioactivity in various tissues of rats were relatively high in the stomach, intestine, liver, kidney, blood, ovary and uterus. Most organs showed the maximum concentrations at 1.5 h, except for intestine, kidney, ovary, and uterus at 6 h. There was no specific tissue retention after 72 h. Two main conjugate metabolites, glucuronide and sulfate of NPC, were detected with free NPC and 2-acetylamino- p-cresol (AAPC) in the urine. NPC was rapidly absorbed and excreted mainly into urine as the conjugate metabolites. A part of NPC was reduced to 2-amino- p-cresol, followed by acetylation to give AAPC.